Early-phase prothrombin time-international normalized ratio in acute liver injury indicates the timing of therapeutic intervention and predicts prognostic improvement.

AIM: We investigated whether an early-phase prothrombin time-international normalized ratio (PT-INR) is an interventional prognostic indicator for patients with acute liver injury, including acute liver failure. METHODS: This was a multicenter retrospective observational study. We included 595 patients with alanine aminotransferase levels ≥300 U/L due to acute liver injury who were admitted to Kagoshima University Hospital or other collaborative investigation organizations between January 1, 2010, and December 31, 2015. Patients with alanine aminotransferase levels ≥300 U/L and no previous liver disease were defined as having an acute liver injury. Acute liver failure was defined by PT-INR ≥1.5 with or without hepatic encephalopathy in acute liver injury patients. Data were obtained retrospectively from case reports and analyzed. RESULTS: The PT-INR on day 1 was the most accurate independent prognosis predictor in patients with acute liver injury and acute liver failure. On day 1, the transplant-free survival rates were significantly lower in patients with PT-INR ≥1.3. The transplant-free survival rates were also significantly higher in patients with acute liver injury and acute liver failure, in whom the PT-INR had recovered from ≥1.3 on day 1 to <1.3 by day 8. CONCLUSION: Early-phase changes in the PT-INR can predict the prognosis of patients with acute liver injury and acute liver failure. Furthermore, PT-INR ≥1.3 could be an interventional marker, whereas PT-INR <1.3 after 1 week could reflect prognostic improvement.

Early Elevation of Cell-Free DNA After Acute Mesenteric Ischemia in Rats.

BACKGROUND: Acute mesenteric ischemia (AMI) is challenging to diagnose in the early phase. We tested the hypothesis that blood levels of cell-free DNA would increase early after AMI. In addition, proteome analysis was conducted as an exploratory analysis to identify other potential diagnostic biomarkers. METHODS: Mesenteric ischemia, abdominal sepsis, and sham model were compared in Sprague-Dawley rats. The abdominal sepsis model was induced by cecum puncture and mesenteric ischemia model by ligation of the superior mesenteric artery. Blood levels of cell-free DNA were measured 2 h and 6 h after wound closure. Shotgun proteome analysis was performed using plasma samples obtained at the 2 h timepoint; quantitative analysis was conducted for proteins detected exclusively in the AMI models. RESULTS: Blood cell-free DNA levels at 2 h after wound closure were significantly higher in the AMI model than in the sham and the abdominal sepsis models (P < 0.05). Cell-free DNA was positively correlated with the pathologic ischemia severity score (correlation coefficient 0.793-0.834, P < 0.001). Derivative proteome analysis in blood at 2-h time point revealed higher intensity of paraoxonase-1 in the AMI models than in the abdominal sepsis models; the significantly high blood paraoxonase-1 levels in the AMI models were confirmed in a separate quantitative analysis (P = 0.015). CONCLUSIONS: Cell-free DNA was demonstrated to be a promising biomarker for the early diagnosis of mesenteric ischemia in a rat model of AMI. Paraoxonase-1 may also play a role in the differential diagnosis of mesenteric ischemia from abdominal sepsis. The current results warrant further investigation in human studies.

Acquisition and Analysis of Microcirculation Image in Septic Model Rats.

Background: Microcirculation is a vital sign that supplies oxygen and nutrients to maintain normal life activities. Sepsis typically influences the operation of microcirculation, which is recovered by the administration of medicine injection. Objective: Sepsis-induced variation and recovery of microcirculation are quantitatively detected using microcirculation images acquired by a non-contact imaging setup, which might assist the clinical diagnosis and therapy of sepsis. Methods: In this study, a non-contact imaging setup was first used to record images of microcirculation on the back of model rats. Specifically, the model rats were divided into three groups: (i) the sham group as a control group; (ii) the cecum ligation and puncture (CLP) group with sepsis; and (iii) the CLP+thrombomodulin (TM) group with sepsis and the application of TM alfa therapy. Furthermore, considering the sparsity of red blood cells (RBCs), the blood velocity is estimated by robust principal component analysis (RPCA) and U-net, and the blood vessel diameter is estimated by the contrast difference between the blood vessel and tissue. Results and Effectiveness: In the experiments, the continuous degradation of the estimated blood velocity and blood vessel diameter in the CLP group and the recovery after degradation of those in the CLP+TM group were quantitatively observed. The variation tendencies of the estimated blood velocity and blood vessel diameter in each group suggested the effects of sepsis and its corresponding therapy.

Multicenter study on the consciousness-regaining effect of a newly developed artificial liver support system in acute liver failure: An on-line continuous hemodiafiltration system.

AIM: Acute liver failure (ALF) patients with coma need to be revived not only for spontaneous recovery but also as a bridge to liver transplantation. We developed a new high-volume plasma purification system using an on-line continuous hemodiafiltration (CHDF) system, and evaluated its safety and efficacy in a multicenter study. METHODS: A single arm interventional study using the new apparatus was undertaken in the six major liver centers in Japan. The primary end-point was the proportion of patients who regained consciousness within 10 days, which was compared with a historical control (47%). Nine ALF patients were enrolled and treated with the new machine. One patient was excluded because of the need for artificial respiration support according to the established protocol. RESULTS: Seven of eight (87.5%) patients regained consciousness during the on-line CHDF session, with five of those seven waking within 4 days. After waking, one patient spontaneously recovered, three received liver transplantation, two died of liver failure, and one died of another disease. The plasma ammonia levels significantly decreased after the start of on-line CHDF from 182.5 ± 64.8 µg/dL (mean ± SD) on day 0 to 87.0 ± 38.9 µg/dL on the last day of the session (P < 0.001). Similarly, the plasma glutamine level also significantly decreased from 2069 ± 1234 µmol/L to 628 ± 193 µmol/L. Although seven severe adverse events occurred during on-line-CHDF, no causal relationship with liver support was recognized. CONCLUSIONS: The newly developed on-line CHDF system showed high efficacy for regain of consciousness and excellent therapeutic safety for managing ALF.

Risk prediction of biomarkers for early multiple organ dysfunction in critically ill patients.

BACKGROUND: Shock and organ damage occur in critically ill patients in the emergency department because of biological responses to invasion, and cytokines play an important role in their development. It is important to predict early multiple organ dysfunction (MOD) because it is useful in predicting patient outcomes and selecting treatment strategies. This study examined the accuracy of biomarkers, including interleukin (IL)-6, in predicting early MOD in critically ill patients compared with that of quick sequential organ failure assessment (qSOFA). METHODS: This was a multicenter observational sub-study. Five universities from 2016 to 2018. Data of adult patients with systemic inflammatory response syndrome who presented to the emergency department or were admitted to the intensive care unit were prospectively evaluated. qSOFA score and each biomarker (IL-6, IL-8, IL-10, tumor necrosis factor-α, C-reactive protein, and procalcitonin [PCT]) level were assessed on Days 0, 1, and 2. The primary outcome was set as MOD on Day 2, and the area under the curve (AUC) was analyzed to evaluate qSOFA scores and biomarker levels. RESULTS: Of 199 patients, 38 were excluded and 161 were included. Patients with MOD on Day 2 had significantly higher qSOFA, SOFA, and Acute Physiology and Chronic Health Evaluation II scores and a trend toward worse prognosis, including mortality. The AUC for qSOFA score (Day 0) that predicted MOD (Day 2) was 0.728 (95% confidence interval [CI]: 0.651-0.794). IL-6 (Day 1) showed the highest AUC among all biomarkers (0.790 [95% CI: 0.711-852]). The combination of qSOFA (Day 0) and IL-6 (Day 1) showed improved prediction accuracy (0.842 [95% CI: 0.771-0.893]). The combination model using qSOFA (Day 1) and IL-6 (Day 1) also showed a higher AUC (0.868 [95% CI: 0.799-0.915]). The combination model of IL-8 and PCT also showed a significant improvement in AUC. CONCLUSIONS: The addition of IL-6, IL-8 and PCT to qSOFA scores improved the accuracy of early MOD prediction.

Very Low Density Lipoprotein Receptor Sequesters Lipopolysaccharide Into Adipose Tissue During Sepsis.

OBJECTIVES: Obese patients have lower sepsis mortality termed the "obesity paradox." We hypothesized that lipopolysaccharide, known to be carried within lipoproteins such as very low density lipoprotein, could be sequestered in adipose tissue during sepsis; potentially contributing a survival benefit. DESIGN: Retrospective analysis. SETTING: University research laboratory. SUBJECTS AND PATIENTS: Vldlr knockout mice to decrease very low density lipoprotein receptors, Pcsk9 knockout mice to increase very low density lipoprotein receptor, and Ldlr knockout mice to decrease low density lipoprotein receptors. Differentiated 3T3-L1 adipocytes. Caucasian septic shock patients. INTERVENTIONS: We measured lipopolysaccharide uptake into adipose tissue 6 hours after injection of fluorescent lipopolysaccharide into mice. Lipopolysaccharide uptake and very low density lipoprotein receptor protein expression were measured in adipocytes. To determine relevance to humans, we genotyped the VLDLR rs7852409 G/C single-nucleotide polymorphism in 519 patients and examined the association of 28-day survival with genotype. MEASUREMENTS AND MAIN RESULTS: Lipopolysaccharide injected into mice was found in adipose tissue within 6 hours and was dependent on very low density lipoprotein receptor but not low density lipoprotein receptors. In an adipocyte cell line decreased very low density lipoprotein receptor expression resulted in decreased lipopolysaccharide uptake. In septic shock patients, the minor C allele of VLDLR rs7852409 was associated with increased survival (p = 0.010). Previously published data indicate that the C allele is a gain-of-function variant of VLDLR which may increase sequestration of very low density lipoprotein (and lipopolysaccharide within very low density lipoprotein) into adipose tissue. When body mass index less than 25 this survival effect was accentuated and when body mass index greater than or equal to 25 this effect was diminished suggesting that the effect of variation in very low density lipoprotein receptor function is overwhelmed when copious adipose tissue is present. CONCLUSIONS: Lipopolysaccharide may be sequestered in adipose tissue via the very low density lipoprotein receptor and this sequestration may contribute to improved sepsis survival.

Population Pharmacokinetic Analysis of Meropenem in Critically Ill Patients With Acute Kidney Injury Treated With Continuous Hemodiafiltration.

BACKGROUND: The aim of this study was to conduct a population pharmacokinetic (PK) analysis of meropenem and to explore the optimal dosing strategy for meropenem in critically ill patients with acute kidney injury receiving treatment with continuous hemodiafiltration (CHDF). METHODS: Blood samples were obtained on days 1, 2, and 5 after the start of meropenem administration, immediately before dosing, and at 1, 2, 6, and 8 hours after dosing. Population PK model analysis was performed and concentration-time profiles were simulated using the Nonlinear Mixed Effects Model software. RESULTS: Twenty-one patients receiving CHDF in our intensive care unit were enrolled and 350 serum concentration-time data points were obtained. The PKs of meropenem were best described using a 2-compartment model. Typical total and intercompartmental clearance values were 4.22 L/h and 7.84 L/h, respectively, whereas the central and peripheral compartment volumes of distribution were 14.82 L and 11.75 L, respectively. Estimated glomerular filtration rate was identified as a significant covariate of meropenem total clearance. In simulations of patients with renal failure receiving CHDF, the dose was affected by estimated glomerular filtration rate; a dose of 0.5 g every 8 hours or 1 g every 12 hours showed the probability of target attainment of achieving 100% time above the minimum inhibitory concentration for bacteria with a minimum inhibitory concentration ≤2 mg/L. CONCLUSIONS: A population PK model was developed for meropenem in critically ill patients with acute kidney injury receiving CHDF. Our results indicated that a meropenem dosage of 0.5 g every 8 hours or 1 g every 12 hours was suitable in this population and for susceptible bacteria.

Impact of increased calls to rapid response systems on unplanned ICU admission.

BACKGROUND: Whether hospital bed number and rapid response system (RRS) call rate is associated with the clinical outcomes of patients who have RRS activations is unknown. We test a hypothesis that hospital volume and RRS call rates are associated with the clinical outcomes of patients with RRSs. METHODS: This is a retrospective chart analysis of an existing dataset associated with In-Hospital Emergency Registry in Japan. In the present study, 4818 patients in 24 hospitals from April 2014 to March 2018 were analyzed. Primary outcome variable was an unplanned intensive care unit (ICU) admission after RRS activation. RESULTS: In the primary analysis of the study using a multivariate analysis adjusting potential confounding factors, higher RRS call rate was significantly associated with decreased unplanned ICU admissions (P < 0.0001, Odds ratio [OR] 0.95, 95% confidence interval [CI] 0.92-0.98), but there was no significant association of hospital volume with unplanned ICU admissions (P = 0.44). In the secondary analysis of the study, there was a non-significant trend of increased cardiac arrest on arrival at the location of the RRS provider at large-volume hospitals (P = 0.084, OR 1.16, 95% CI 0.98-1.38). Large-volume hospitals had a significantly higher 1-month mortality rate (P = 0.0040, OR 1.10, 95% CI 1.03-1.18). CONCLUSION: Hospitals with increased RRS call rates had significantly decreased unplanned ICU admission in patients who had RRS activations. Patients who had RRS activations at large-volume hospitals had an increased 1-month mortality rate.

Changes in acute blood purification therapy in critical care: republication of the article published in the Japanese Journal of Artificial Organs.

Acute blood purification therapy is an essential artificial organ in critical care. In the review article, looking back on the history, we describe our present knowledge and techniques of acute blood purification therapy in critical care. The topics include continuous hemodiafiltration (CHDF), online HDF as an artificial liver support, blood purification therapy aiming to remove pathogenic substances of sepsis, a procedure for connecting a CRRT device into an extra-corporeal membrane oxygenation circuit, and replacement fluid for CHDF. We also raise remaining issues and clarify the future direction of acute blood purification therapy in critical care. This review was created based on a translation of the Japanese review written in the Japanese Journal of Artificial Organs in 2017 (Vol. 46, No. 1, pp. 67-70), with adding some references.

A CO2 removal system using extracorporeal lung and renal assist device with an acid and alkaline infusion.

The patients with respiratory failure need high tidal volume by mechanical ventilation, which lead to the ventilator-induced lung injury. We developed an extracorporeal lung and renal assist device (ELRAD), comprising acid infusion, membrane lung, continuous hemodiafiltration and alkaline infusion. To evaluate this system, we conducted in vivo studies using experimental swine which were connected to the new system. In vivo experiments consist of four protocols; baseline = hemodiafiltration only (no O2 gas flow to membrane lung); membrane lung = "Baseline" plus O2 gas flow to membrane lung; "Acid infusion" = "Membrane lung" plus continuous acid infusion; ELRAD = "Acid infusion" plus continuous alkaline infusion. We changed the ventilatory rate of the mechanical ventilation to maintain PCO2 at 50-55 mmHg during the four protocols. The results showed that there was statistically no significant difference in the levels of pH, HCO3-, and base excess when each study protocol was initiated. The amount of CO2 eliminated by the membrane lung significantly increased by 1.6 times in the acid infusion protocol and the ELRAD protocol compared to the conventional membrane lung protocol. Minute ventilation in the ELRAD protocol significantly decreased by 0.5 times compared with the hemodiafiltration only protocol (P < 0.0001), the membrane lung (P = 0.0006) and acid infusion protocol (P = 0.0017), respectively. In conclusion, a developed CO2 removal system efficiently removed CO2 at low blood flow and reduced minute ventilation, while maintaining acid-base balance within the normal range.

High recovery rate of consciousness by high-volume filtrate hemodiafiltration for fulminant hepatitis.

AIM: An artificial liver support (ALS) system sustaining patients with acute liver failure (ALF) in good condition until recovery of the native liver or performance of liver transplantation (LT), is essential for the improvement of the poor prognosis of ALF despite the lack of survival benefit. We aimed to investigate the efficacy of various ALS systems for fulminant hepatitis (FH) carried out in our liver unit so far, focusing on the restoration of consciousness from hepatic encephalopathy. METHODS: One hundred and ten consecutive adult Japanese patients with FH admitted to Chiba University Hospital (Chiba, Japan) between 1988 and 2016 who received ALS were analyzed. RESULTS: Recovery rate of consciousness improved with the increased dialysate flow rate and filtrate rate: 37.5% by plasma exchange (PE), 51.9% by PE + continuous hemodiafiltration (CHDF), 57.7% by slow PE (sPE) + high-flow CHDF (HFCHDF) (QD = 300 mL/min), 88.6% by HFCHDF (QD = 500 mL/min) (+ sPE), and 92.9% by on-line HDF (OLHDF) (+ sPE). All patients except one, who could not be fully treated because of circulatory failure, recovered consciousness by OLHDF, including those whose liver function were completely abolished. Superiority of HFCHDF (QD = 500 mL/min) and OLHDF was also shown in patients who died without LT or received LT. CONCLUSIONS: More effective ALS should be recognized considering the extremely high recovery rate of consciousness. In particular, OLHDF with predilution reduces the cost of substitution fluid by supplying an unlimited amount of dialysate as substitution fluid prepared using an on-line system, and simplifies the procedure for the management.

Interleukin-6 as a diagnostic marker for infection in critically ill patients: A systematic review and meta-analysis.

BACKGROUND: The ability of blood levels of interleukin (IL)-6 to differentiate between infection and non-infection in critically ill patients with suspected infection is unclear. We assessed the diagnostic accuracy of serum IL-6 levels for the diagnosis of infection in critically ill patients. METHODS: We systematically searched the PubMed, MEDLINE, Cochrane Resister of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, and Igaku Chuo Zasshi databases for studies published from 1986 to August 2016 that evaluated the accuracy of IL-6 levels for the diagnosis of infection. We constructed 2 × 2 tables and calculated summary estimates of sensitivity and specificity using a bivariate random-effects model. RESULTS: The literature search identified 775 articles, six of which with a total of 527 patients were included according to the predefined criteria. The pooled sensitivity, specificity, and diagnostic odds ratio were 0.73 (95% confidence interval [CI], 0.61-0.82), 0.76 (95% CI, 0.61-0.87), and 2.31 (95% CI, 1.20-3.48), respectively. The area under the curve (AUC) of the summary receiver operator characteristic (SROC) curve was 0.81 (95% CI, 0.78-0.85). In the secondary analysis of two studies with a total of 263 adult critically ill patients with organ dysfunction, the pooled sensitivity, specificity, and diagnostic odds ratio were 0.81 (95% CI, 0.75-0.86), 0.77 (95% CI, 0.67-0.84), and 2.87 (95% CI 2.15-3.60), respectively. CONCLUSIONS: Blood levels of IL-6 have a moderate diagnostic value and a potential clinical utility to differentiate infection in critically ill patients with suspected infection.

Association between serum levels of interleukin-6 on ICU admission and subsequent outcomes in critically ill patients with acute kidney injury.

BACKGROUND: Exacerbated inflammatory response is considered one of the key elements of acute kidney injury (AKI). Interleukin-6 (IL-6) is an inflammatory cytokine that plays important roles in the inflammatory response and may be useful for predicting the clinical outcomes in patients with AKI. However, supporting evidence adapted to the current KDIGO criteria is lacking. METHODS: AKI patients admitted to the ICU between Jan 2011 and Dec 2015 were retrospectively screened. Patients were assigned to three groups by admission IL-6 tertiles. Associations between IL-6 on ICU admission and in-hospital 90-day mortality, short-term/long-term renal function were analyzed. RESULTS: Patients (n = 646) were divided into low (1.5-150.2 pg/mL), middle (152.0-1168 pg/mL), and high (1189-2,346,310 pg/mL) IL-6 on ICU admission groups. Patients in the high IL-6 group had higher in-hospital 90-day mortality (low vs. middle vs. high, P = 0.0050), lower urine output (low vs. middle vs. high, P < 0.0001), and an increased probability of persistent of anuria for ≥12 h (low vs. middle vs. high, P < 0.0001) within 72 h after ICU admission. In contrast, the high IL-6 group had a lower incidence of persistent AKI at 90 days after the ICU admission in survivors (low vs. middle vs. high, P = 0.013). CONCLUSIONS: Serum levels of IL-6 on ICU admission may predict short-term renal function and mortality in AKI patients and were associated with renal recovery in survivors.

Non-invasive monitoring using photoplethysmography technology.

We evaluated the accuracy and precision of a novel non-invasive monitoring device in comparison with conventional monitoring methods used in intensive care units (ICU). The study device was developed to measure blood pressure, pulse rate, respiratory rate, and oxygen saturation, continuously with a single sensor using the photoplethysmographic technique. Patients who were monitored with arterial pressure lines in the ICU were enrolled. Systolic and diastolic blood pressure, pulse rate, respiratory rate, and arterial oxygen saturation were measured continuously for 30 min at 5-min intervals using the conventional methods and the study device. The primary outcome variable was blood pressure. Blood pressure measured by the study device highly correlated with the arterial pressure line values (correlation coefficients > 0.95). Percent errors for systolic, diastolic and mean blood pressures were 2.4% and 6.7% and 6.5%, respectively. Percent errors for pulse rate, respiratory rate and oxygen saturation were 3.4%, 5.6% and 1.4%, respectively. The non-invasive, continuous, multi-parameter monitoring device presented high level of agreement with the invasive arterial blood pressure monitoring, along with sufficient accuracy and precision in the measurements of pulse rate, respiratory rate, and oxygen saturation.

Corticosteroid might reduce serum levels of pro-inflammatory cytokines in fulminant hepatitis: A case series.

AIM: There are no beneficial therapies except for emergency liver transplantation for acute liver failure (ALF). However, in Japan, which has a serious problem in the shortage of donor livers, therapies other than transplantation must be further investigated for patients with ALF. Pro-inflammatory cytokines promoting tissue destruction are predominant at an early phase of ALF. Corticosteroid (CS) influences monocyte/macrophage differentiation, by suppressing pro-inflammatory genes, indicating CS treatment might be beneficial during the early phase of ALF. Our aim was to elucidate the efficacy of CS pulse therapy in decreasing pro-inflammatory cytokine levels in the early stage of ALF. METHODS: Ten consecutive adult Japanese patients with fulminant hepatitis in the early stage, three treated with artificial liver support (ALS) and CS pulse therapy (ALS + CS group) and seven treated with ALS (ALS group), were enrolled. Clinical and biochemical data on admission were matched between the groups and retrospectively analyzed for serum concentrations of interleukin-6, tumor necrosis factor-α, and interleukin-1ß over a 2-week period. RESULTS: Mean cytokine levels on admission were not different between the two groups. Tumor necrosis factor-α was significantly reduced on day 7 in patients with CS. Serum levels of pro-inflammatory cytokines tended to be reduced in patients with CS compared to those without during the observation period, although the differences were not significant. CONCLUSIONS: It might be possible that introduction of CS pulse therapy in the early stage of ALF could reduce levels of pro-inflammatory cytokines, which might inhibit the cascade of progression of ALF.

Efficient CO2 removal using extracorporeal lung and renal assist device.

We developed a novel system comprising acid infusion, membrane lung, and a continuous renal replacement therapy console for efficient CO2 removal at a low blood flow. To evaluate the new system, we used an ex vivo experimental model using swine blood. A liter of aliquoted blood adjusted to pH 7.25 and pCO2 65 mm Hg was mixed with acid (0, 10, or 20 mL of lactic or hydrochloric acid [1 mol/L]) and was immediately delivered to the system in a single pass. We collected blood samples at each point of the circuit and calculated the amount of CO2 eliminated by the membrane lung. The new system removed 13.2 ± 0.8, 32.0 ± 2.1, and 51.6 ± 3.7 mL/min of CO2 (with 0, 10, and 20 mEq/L of lactic acid) and 21.2 ± 1.2, 27.3 ± 0.3, and 42.0 ± 1.3 mL/min (with 0, 10, and 20 mEq/L of hydrochloric acid), respectively. The levels of lactate and Cl- ions for acid-base equilibrium were restored after continuous hemodiafiltration. Thus, the amount of CO2 eliminated by the membrane lung was 3.9 times higher with lactic acid and 2.0 times higher with hydrochloric acid compared with non-acid controls. In conclusion, this easy-to-setup CO2 removal system was safe, effective, and removed CO2 at a low blood flow.

Estimation of population-level effect of the endocrine disruptor pyriproxyfen in Daphnia magna by using changes in sex ratio and reproductive output.

Here we developed an analytical means of estimating population-level effects of endocrine disruptors on Daphnia magna. Our approach was based on the fact that the endocrine-disrupting juvenile hormone analogs induce the production of male neonates if they are exposed to the analogs during a particular period in their prenatal development; the method also assumed that the abnormal production of male neonates in the sake of production of female neonates reduces population growth. We constructed a linear toxicodynamics model to elucidate the period in which D. magna neonates are sensitive to exposure to the analog and also the probability of an individual neonate changing sex under specific exposure concentrations. The proposed model was applied to D. magna reproduction test data obtained under time-varying exposure to pyriproxyfen to derive the maximum-likelihood estimates and the posterior distributions of the model parameters. To quantitatively assess the ecological risk at the population level, we conducted a population dynamics simulation under two time-varying exposure scenarios (i.e., constant or pulsed exposure) by using an age-structured population model. When the change in sex ratio was based on the time-weighted average concentration during the period of sensitivity, change in sex ratio caused approximately equivalent population-level effects as did reproductive inhibition (i.e., reduction in the total number of neonates per female parent) regardless of the exposure scenario. In contrast, when change in sex ratio was based on maximum concentration during the sensitive period, change in sex ratio caused only half the population-level effects as did reproductive inhibition under constant exposure, whereas it caused a much larger population-level effect than did reproductive inhibition under pulsed exposure.

Suppression of T Cell Autophagy Results in Decreased Viability and Function of T Cells Through Accelerated Apoptosis in a Murine Sepsis Model.

OBJECTIVE: While type 1 programmed cell death (apoptosis) of T cells leads to immunosuppression in sepsis, a crosstalk between apoptosis and autophagy (type 2 programmed cell death) has not been shown. The aim of this study is to elucidate the details of the interaction between autophagy and immunosuppression. DESIGN: Laboratory investigation in the murine sepsis model. SETTING: University laboratory. SUBJECTS: Six- to 8-week-old male mice. INTERVENTIONS: We investigated the kinetics of autophagy in T cells from spleen in a cecal ligation and puncture model with green fluorescent protein-microtubule-associated protein light chain 3 transgenic mice. We analyzed apoptosis, mitochondrial homeostasis and cytokine production in T cells, and survival rate after cecal ligation and puncture using T cell-specific autophagy-deficient mice. MEASUREMENTS AND MAIN RESULTS: We observed an increase of autophagosomes, which was assessed by flow cytometry. However, an autophagy process in CD4 T cells during sepsis was insufficient including the accumulation of p62. On the other hand, a blockade of autophagy accelerated T cell apoptosis compared with the control mice, augmenting the gene expression of Bcl-2-like 11 and programmed cell death 1. Furthermore, mitochondrial accumulation in T cells occurred via a blockade of autophagy during sepsis. In addition, interleukin-10 production in CD4 T cells from the cecal ligation and puncture-operated knockout mice was markedly increased. Consequently, deficiency of autophagy in T cells significantly decreased the survival rate in the murine sepsis model. CONCLUSIONS: We demonstrated that blocking autophagy accelerated apoptosis and increased mortality in concordance with the insufficient autophagy process in CD4 T cells in the murine sepsis model, suggesting that T cell autophagy plays a protective role against apoptosis and immunosuppression in sepsis.

An extremely high bioavailability of orally administered vancomycin in a patient with severe colitis and renal insufficiency.

Because there is little absorption of orally administered vancomycin hydrochloride (VCM) through the normal intestinal microvillus membrane, the pharmacokinetics of VCM absorbed from the digestive tract are mostly unknown. Here we report a case of severe colitis and renal insufficiency in which the serum concentration of VCM reached the supratherapeutic range after oral administration. A 54-year-old man receiving outpatient chemotherapy for rectal cancer was admitted to our hospital for severe sepsis and acute renal failure. Multimodal therapy including continuous renal replacement therapy (CRRT) and mechanical ventilation was initiated, and oral VCM administration (0.5 g every 6 h) was begun for suspected severe pseudomembranous colitis with large amounts of watery stool. Despite continued CRRT, the serum VCM concentration increased to 30.6 µg/mL after 4 days. Based on pharmacokinetic analysis, the bioavailability of VCM was estimated to be over 54.5%. Colonoscopy showed that the mucosa was severely damaged throughout the large intestine, resulting in considerable exudation of plasma and blood. This case indicates the need for careful and early monitoring during high-dose oral VCM administration to patients with severe mucosal injury and renal insufficiency.

A safe procedure for connecting a continuous renal replacement therapy device into an extracorporeal membrane oxygenation circuit.

Patients receiving extracorporeal membrane oxygenation (ECMO) often require continuous renal replacement therapy (CRRT). The intra-circuit pressure of adult ECMO usually deviates from the physiological range. We investigated the use of CRRT connected to an ECMO circuit with physiological intra-circuit pressures (0-150 mmHg, defined as the "safety range") using an in vitro experiment involving a water-filled ECMO circuit. The intra-circuit pressure pre-pump, post-pump, and post-oxygenator were measured while varying the height of the pump or ECMO flow. The bypass conduit pressure and distance from the post-oxygenator port were measured to find the "safety point", where the bypass pressure remained within the safety range. Both drainage and return limbs of the CRRT machine were connected to the safety point and the inlet and outlet pressures of the hemofilter were recorded while varying the ECMO and CRRT flow. The pre-pump pressure only remained within the safety range for heights >75 cm (ECMO flow = 4 L/min) or ECMO flow <3.5 L min (height = 50 cm). The post-pump and post-oxygenator pressure was generally outside of the safety range. The bypass pressure decreased according to the distance from the post-oxygenator port and the safety point was found at 60 or 75 cm (in a 90-cm length conduit) regardless of ECMO flow. The hemofilter inlet and outlet pressures remained within the safety range for all conditions of ECMO and CRRT flow, findings validated in clinical cases. The bypass conduit within an ECMO circuit can be connected to a CRRT machine safely under physiological pressures in adult patients receiving ECMO.